The specific features of the developing T cell compartment of the neonatal lung are a determinant of respiratory syncytial virus immunopathogenesis

PLoS Pathog. 2021 Apr 28;17(4):e1009529. doi: 10.1371/journal.ppat.1009529. eCollection 2021 Apr.

Abstract

The human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, possibly due to the properties of the immature neonatal pulmonary immune system. Using the newborn lamb, a classical model of human lung development and a translational model of RSV infection, we aimed to explore the role of cell-mediated immunity in RSV disease during early life. Remarkably, in healthy conditions, the developing T cell compartment of the neonatal lung showed major differences to that seen in the mature adult lung. The most striking observation being a high baseline frequency of bronchoalveolar IL-4-producing CD4+ and CD8+ T cells, which declined progressively over developmental age. RSV infection exacerbated this pro-type 2 environment in the bronchoalveolar space, rather than inducing a type 2 response per se. Moreover, regulatory T cell suppressive functions occurred very early to dampen this pro-type 2 environment, rather than shutting them down afterwards, while γδ T cells dropped and failed to produce IL-17. Importantly, RSV disease severity was related to the magnitude of those unconventional bronchoalveolar T cell responses. These findings provide novel insights in the mechanisms of RSV immunopathogenesis in early life, and constitute a major step for the understanding of RSV disease severity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Child, Preschool
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Lung / growth & development
  • Lung / immunology*
  • Lung / pathology
  • Lung / virology
  • Respiratory Syncytial Virus Infections / congenital
  • Respiratory Syncytial Virus Infections / immunology*
  • Respiratory Syncytial Virus Infections / pathology
  • Respiratory Tract Infections / congenital
  • Respiratory Tract Infections / immunology*
  • Respiratory Tract Infections / pathology
  • Sheep / growth & development
  • Sheep / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology*
  • T-Lymphocytes / physiology

Grants and funding

T.D. was supported in part by the EU FP7 Project UniVax (HEALTH-F3-2013-60173). This project was funded by the Swiss National Science Foundation (grant No. 310030_172895 to M.P.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.